The present invention relates to novel pharmaceutical compounds and their synthesis, the compounds being retinoids having utilities analogous to those for naturally-occurring vitamin A.
Vitamin A naturally occurs in three common forms, vitamin A alcohol (retinol), vitamin A aldehyde (retinal) and vitamin A acid (retinoic acid). All forms are isoprenoid compounds containing a six-membered carbocyclic ring and an eleven-carbon side chain.
Vitamin A occurs in solution as a mixture of nearly planar 6-s-trans and distorted 6-s-cis conformations, with the latter conformation predominating (shown below for retinal): ##STR2##
An analog of retinal has been proposed which has a conformationally-defined, distorted 6-s-cis geometry (see Robinson et al., "Reactions of Vinylogous Phosphonate Carbanions and Reformatsky Reagents with a Sterically Hindered Ketone and Enone", The Journal of Organic Chemistry 54: 1992-1997, 1989): ##STR3## A precursor to this retinal analog has been reported in this publication.
Since vitamin A is known to play a role in the visual cycle in vertebrates, vitamin A and its analogs have been used to treat vision-related problems. Vitamin A has also been associated with bioactive properties useful in cancer chemoprevention, chemotherapy, treatment of dermatological disorders (e.g., with "Retin-A".TM. and "Accutane".TM.) and immunostimulation. However, the therapeutic index of vitamin A, which is a function of its potency and toxicity, limits the applications thereof.